TRT Systematic Review Report

Transcription

Testosterone in the treatment of androgen
deficiency
Systematic Review and Network Meta-Analysis
George Wells, Jesse Elliott, Shannon Kelly, Joan Peterson, Amy Johnston,
Ahmed Kotb, Li Chen, Becky Skidmore
November 17, 2014
Note
Some details are censored in this report so as not to preclude publication. Publications (when available) and/or final
unpublished reports will be available on the ODPRN website (www.odprn.ca).
30 Bond Street, Toronto ON, M5B 1W8
www.odprn.ca
[email protected]
2
Table of Contents
List of exhibits………………………………………………………………………………………………………………………………………….4
Efficacy and Safety Systematic Review ......................................................................................................... 5
Results ........................................................................................................................................................... 7
Efficacy .......................................................................................................................................................... 8
Serum testosterone level........................................................................................................................ 10
Quality of life........................................................................................................................................... 11
Erectile dysfunction ................................................................................................................................ 12
Libido....................................................................................................................................................... 13
Depression .............................................................................................................................................. 14
Fractures ................................................................................................................................................. 15
Activities of daily living............................................................................................................................ 15
Comparisons among the testosterone replacement therapies.................................................................. 15
Safety .......................................................................................................................................................... 16
Cardiovascular death .............................................................................................................................. 16
Myocardial infarction.............................................................................................................................. 17
Stroke ...................................................................................................................................................... 19
Newly diagnosed disease ........................................................................................................................ 20
a)
Prostate cancer ........................................................................................................................... 20
b)
Diabetes ...................................................................................................................................... 22
c)
Heart disease .............................................................................................................................. 22
Serious adverse events ........................................................................................................................... 23
Erythrocytosis ......................................................................................................................................... 24
Skin reactions .......................................................................................................................................... 24
Non-Randomized Studies............................................................................................................................ 25
Skin reactions .......................................................................................................................................... 27
Key Messages .............................................................................................................................................. 28
Report Reference List.................................................................................................................................. 30
Appendix A: Included Randomized Controlled Trial List............................................................................. 34
Ontario Drug Policy Research Network
3
Appendix B: Characteristics of Included RCTs............................................................................................. 37
Appendix C: Head-To-Head Comparisons — Network Meta-Analysis ....................................................... 42
Appendix D: Reported Skin Reaction in RCTs ............................................................................................. 45
Appendix E: Included Non-Randomized Study List ..................................................................................... 47
Appendix F: Characteristics of Included Non-Randomized Studies ............................................................ 49
4
List of Exhibits
Exhibit 1: Summary of randomized controlled trial characteristics…………………………………………………………………………..7
Exhibit 2: Dose and routes of administration of testosterone replacement therapy…………………………………………………8
Exhibit 3: Evidence network for serum testosterone level at 3 months……………………………………………………………………9
Exhibit 4: Serum testosterone level, quality of life, erectile dysfunction, libido, and depression: mean (SD)
differences from placebo based on network meta-analysis……………………………………………………………………………………10
Exhibit 5: Summary of studies that reported quality of life…………………………………………………………………………………....11
Exhibit 6: Summary of studies that reported erectile dysfunction………………………………………………………………………….12
Exhibit 7: Summary of studies that reported libido………………………………………………………………………………………………..13
Exhibit 8: Summary of studies that reported depression………………………………………………………………………………………..14
Exhibit 9: Head-to-head comparisons of the testosterone treatments on serum testosterone level
at 3 months……………………………………………………………………………………………………………………………………………….…………. 16
Exhibit 10: Cardiovascular death: odds ratios of any testosterone compared to placebo……………………………………….17
Exhibit 11: Cardiovascular death: odds ratios of testosterone gel compared to placebo………………………………………..17
Exhibit 12: Myocardial infarction: odds ratios of any testosterone compared to placebo………………………………………18
Exhibit 13: Myocardial infarction: odds ratios of testosterone gel compared to placebo……………………………………….19
Exhibit 14: Stroke: odds ratios of any testosterone compared to placebo………………………………………………………………20
Exhibit 15: Stroke: odds ratios of testosterone gel compared to placebo………………………………………………………………20
Exhibit 16: Prostate Cancer: odds ratios of any testosterone compared to placebo……………………………………………….21
Exhibit 17: Prostate Cancer: odds ratios of testosterone gel compared to placebo………………………………………………..21
Exhibit 18: Prostate Cancer: odds ratios of IM testosterone compared to placebo…………………………………………………22
Exhibit 19: Serious Adverse Events: odds ratios of testosterone gel compared to placebo…………………………………….23
Exhibit 20: Included non-randomized studies that reported at least one safety outcome of interest…………………….26
Exhibit 21: Skin reactions reported in included non-randomized studies……………………………………………………………….27
5
Efficacy and Safety Systematic Review
The strategy for building and analyzing the evidence base for the use of testosterone in men with low
testosterone consisted of two fundamental steps:
A broad systematic review and pair-wise meta-analysis of the available randomized evidence in the
published and grey literature conducted following the methods and procedures outlined in the
Cochrane Handbook for Systematic Reviews for Interventions (1).
A Bayesian network meta-analysis of randomized evidence conducted relating Health Canada–approved
testosterone products in a network, for each of the benefit and safety outcomes specified a priori. The
methods and procedures followed are those developed by the Canadian Collaboration for Drug Safety,
Effectiveness and Network Meta-Analysis (ccNMA), funded by the Drug Safety and Effectiveness
Network (DSEN) of the Canadian Institute of Health Research.
A protocol was developed using guidance from the PRISMA Statement (2) and following the methods
and procedures outlined in the Cochrane Handbook for Systematic Reviews for Interventions (1). It was
peer-reviewed by experts in pharmacology, biostatistics, and systematic review methodology.
Electronic search strategies were developed and tested through an iterative process by an experienced
medical information specialist in consultation with the review team. The database searches were
executed on 8 June 2014. Using the OVID platform, we searched Ovid MEDLINE, Ovid MEDLINE InProcess & Other Non-Indexed Citations, and Embase Classic+Embase on June 3, 2014. We also searched
CENTRAL in the Cochrane Library on Wiley on the same date. Strategies utilized a combination of
controlled vocabulary (e.g., testosterone, androgens, androgen therapy) and keywords (e.g., delatestryl,
testosterone supplementation, testosterone replacement therapy). Vocabulary and syntax were
adjusted across the databases. We used research design filters to identify randomized, non-randomized
and controlled clinical trials, as well as observational (comparative) studies. A separate search for
systematic reviews was performed on June 8, 2014. A grey literature search of relevant databases and
web sites was performed using resources listed in CADTH’s Grey Matters Light
(www.cadth.ca/en/resources/finding-evidence-is/grey-matters/grey-matters-light).
Studies were eligible for inclusion in the systematic review if they satisfied the population, intervention,
and comparator, as well as the study designs of interest.
6
The study population consisted of adult men with low testosterone, satisfying the following eligibility
criteria:
Population
Adult men with androgen deficiency (serum total testosterone ≤ 12 nmol/L)
Index Node
Placebo
Comparisons
Testosterone replacement therapies currently available in Canada: testosterone undecanoate
(Andriol), testosterone cypionate (Depo-Testosterone), testosterone enanthate (Delatestryl),
testosterone (Androderm, Testim 1%, Androgel 1%, Axiron).
• Testosterone replacement therapy (TRT) v. placebo
• TRT v. TRT (same TRT at different dose or different TRT)
• Self-administered or administered by health care provider
• Health Canada–approved daily doses
• All routes of administration
Outcomes:
Efficacy
Outcomes:
Safety
Study Types:
Efficacy
Study Types:
Safety
Exclusions
•
•
•
Serum testosterone level
Quality of life
Resolution of symptoms:
• Erectile dysfunction
• Libido improvement
• Depression
• Fractures
• Activities of daily living
• Cardiovascular death
• Myocardial infarction
• Stroke
• Erythrocytosis
• Serious adverse events
• Newly diagnosed disease (diabetes, heart disease, or prostate cancer)
• Skin or site reactions
Randomized controlled trials (RCTs)
RCTs and non-randomized studies with a comparator
•
•
•
•
•
•
Studies not conducted in English
Testosterone products or delivery formulations (e.g., buccal cavity, implantable pellets)
not currently approved by Health Canada.
Studies published only in abstract format
Uncontrolled non-randomized studies
Studies involving less than 10 men
Duration shorter than 3 months
Data from crossover designs were used if the first period results were reported and if the duration of the
7
initial treatment was 3 months duration or longer.
Results
A total of 39 unique randomized controlled trials (in 55 publications) were identified in the systematic
review (Appendix A, Appendix B; Exhibit 1). Studies were published between 1992 and 2014 and included
adult men with total serum testosterone level of 12 nmol/L or lower. There was a mixture of funding of
the included trials: some were funded by pharmaceutical companies, while others were funded by nonpharmaceutical entities. Twenty studies (3-22) were conducted in the United States; one was conducted
in Canada (23). Fourteen studies (3, 6, 10, 11, 13, 15, 21-28) required participants to have symptoms of
testosterone deficiency as an inclusion criteria for enrollment in the study; the other studies required no
symptoms or did not report whether symptoms were required for study enrollment.
The included studies had a wide range of primary outcomes, ranging from the efficacy of testosterone
on improving bone mineral density to improving erectile function to improving cognitive function. Seven
studies (4, 5, 7, 9, 21, 25, 29) reported a measure of physical fitness as their primary outcome (e.g.,
muscle strength as measured by leg press, lean body mass).
The total number of participants in each study ranged from 10 to 406. The overall number of included
participants was 3243, and participants ranged from 20 to 95 years of age. Participants were both
treatment naïve and experienced; most studies required a washout period if TRT had been used before
enrollment (duration of washout period varied by route of administration).
Exhibit 1: Summary of randomized controlled trial characteristics
Trial characteristic
Publication status
Category
No. of included studies
Literature sources
55
Unique RCTs
39
Canada
1
US
20
Multi-national
2
Parallel
34
Factorial
3
Cross-over
2
Pharmaceutical
6
Non-Pharmaceutical
11
Mixed
7
Not reported
15
Publication year
--
1992 to 2014
No. randomized
--
10 to 406
Country
Study design
Sponsors
8
A variety of doses and routes of administration were found in the included studies (Exhibit 2).
Exhibit 2: Dose and routes of administration of testosterone replacement therapy
TRT product
Included doses
Route
Brand specified
Andriol
20 mg/d, 40 mg/d, 120–160 mg/d
Oral
Depo-Testosterone
No studies
Intramuscular injection
Delatestryl
125 mg/wk, 150 mg/2 wk, 200 mg/2 wk
Androderm
5 mg/d
Patch
Testim 1%
50–150 mg/d
Topical gel
Androgel 1%
5 mg/d, 25–100 mg/d
Topical gel
Axiron
No studies
Topical solution
Testosterone gel
125 mg/d
Topical gel
Testosterone enanthate
100 mg/wk, 200 mg/2wk, 50–400 mg/1–2
wk, 250 mg/3wk, 300 mg/3wk
Testosterone undecanoate
160 mg/d
Oral
Testosterone cypionate
200 mg/2wk
Brand not specified
No studies involving Axiron were eligible for inclusion. The references provided by Eli Lilly as part of their
evidence submission package were not eligible because they did not fulfill one or more of the PICO
criteria (e.g., no comparison group, involved women, review).
Efficacy
Network meta-analyses were conducted for 5 efficacy outcomes: serum testosterone level, quality of
life, erectile dysfunction, libido, and depression. The choice of these outcomes for network metaanalysis was based on their importance and the sufficiency of the data available to derive robust and
consistent network models.
As an illustration, the evidence network for serum testosterone level at 3 months considered in the
network meta-analysis is provided in Exhibit 3.
9
Exhibit 3: Evidence network for serum testosterone level at 3 months
A variety of doses and routes of administration were found in the included studies. Treatment nodes in
the network were assigned based on product brand name if available and by generic formulation if
brand names were not available. Trial dosing strategies were not collapsed for nodes except where
specifically noted in this report. Certain nodes may contain adjunct medications (e.g. sildenifil);
however, this is noted in the treatment name assigned to the node.
A summary of the efficacy results for outcomes where network meta-analysis was conducted are
provided in Exhibit 4. In general:
•
•
•
•
•
Several of the testosterone replacement therapies were associated with a substantive increase
in serum testosterone levels at 3 months.
No significant improvements in quality of life were identified.
No significant improvements in erectile dysfunction were identified.
No significant improvement in libido were identified.
No significant effects on depression were identified.
10
Exhibit 4: Serum testosterone level, quality of life, erectile dysfunction, libido, and depression: mean (SD) differences from
placebo based on network meta-analysis
Mean difference (SD)
Treatment
Serum
testosterone
level, 3 mo
Quality of life
1
Erectile
2
dysfunction
Libido
3
Depression
4
Androderm, patch, 5 mg/d
5.38 (2.54)*
---
---
–0.94 (4.26)
–2.01 (4.75)
Androgel 1%, gel, 50 mg/d
10.38 (2.72)*
1.53 (19.54)
3.29 (8.31)
–1.65 (4.30)
0.02 (3.41)
---
---
---
---
1.05 (18.87)
1.40 (11.41)
0.28 (5.24)
---
Testim 1%, gel, 50–150 mg/d + sildenafil
*
18.49 (3.42)
*
10.24 (2.84)
Testim 1%, gel, 50 mg/d
2.28 (2.81)
---
---
–0.14 (5.03)
---
7.53 (3.51)*
2.49 (19.16)
---
---
–0.69 (3.43)
---
---
0.97 (5.22)
---
15.67 (3.91)
---
---
---
---
6.30 (3.19)
---
---
---
---
---
---
---
–2.29 (3.36)
Andriol, oral, 120 mg/d
Delatestryl, IM, 200 mg/2wk
Testosterone enanthate, IM, 100 mg/wk
4.34 (2.68)
*
*
Testosterone enanthate, IM, 200 mg/2wk
8.65 (2.91)
Testosterone cypionate, IM, 200 mg/2wk
–0.18 (3.27)
---
---
---
---
---
–0.77 (13.51)
–0.13 (11.48)
–1.11 (5.18)
---
Testim 1%, gel, 100 mg/d
---
---
---
0.51 (7.31)
---
Andriol, oral, 120–160 mg/d
---
–18.78 (18.97)
---
---
---
Testosterone undecanoate, oral, 160 mg/d
---
–0.29 (19.35)
3.62 (8.18)
---
–3.10 (3.39)
---
---
---
---
–4.08 (3.40)
Testosterone enanthate, IM, 300 mg/3wk
---
---
---
---
–1.20 (3.38)
---
–3.16 (18.78)
---
---
---
Note: IIEF = International Index of Erectile Function, IM = intramuscular injection, SD = standard deviation, SMD = standardized mean difference.
1. SMD translated to Aging Male Symptoms (AMS) Rating Scale.
2. SMD translated to IIEF erectile dysfunction domain.
3. SMD translated to IIEF sexual desire domain.
4. SMD translated to Beck Depression Inventory.
*Statistically significant (p < 0.05).
Serum testosterone level
Of the included studies, 32 (3, 4, 6-18, 20, 21, 23-37) reported serum testosterone levels after
treatment. At three months, 15 studies reported testosterone levels (3, 7, 10, 12, 13, 15, 18, 20, 24, 26,
27, 29, 32, 34, 35). In particular, Androderm (patch, 5 mg/d), Androgel 1% (gel, 50 mg/d, 75 mg/d, 100
mg/d), Testim 1% (gel, 50–150 mg/d plus sildenafil), Delatestryl (IM, 200 mg/2wk), and testosterone
enanthate (IM, 200 mg/2wk) were associated with a substantive increase in serum testosterone levels at
3 months. The largest increase in serum testosterone was for Androgel 1% (100 mg/d) and Delatestryl
(IM, 200 mg/2wk) (Exhibit 4).
11
Quality of life
Ten studies assessed the efficacy of testosterone replacement therapy on participants’ quality of life (3,
6, 8, 10, 13, 23-25, 36, 38). These studies used many different quality of life outcome scales to evaluate
this outcome: the Aging Male Symptoms Rating Score, Short-Form Health Survey (both the Short Form
12 and 36 version), Questions on Life Satisfaction, Health Related Quality of Life survey, International
Prostate Symptom Score (quality of life subscale), University of California Los Angeles Prostate Index
Questionnaire (sexual function–related quality of life subscale), Quality of Life Enjoyment and
Satisfaction Questionnaire, and Quality of Life Enjoyment and Satisfaction Questionnaire (39). Two
studies were excluded from this analysis because they did not provide sufficient data for analysis (3, 29).
The results were available for 6 treatments and reported in the units of the Aging Male Symptoms
Rating Score in Exhibit 4. No significant improvements in quality of life were identified. However, the
study by Zhang and colleagues (24) found a significant improvement in quality of life for Andriol, oral
120–160 mg/d compared to placebo; the original data are shown in Exhibit 5.
Exhibit 5: Summary of studies that reported quality of life
After treatment,
mean (SD)
Study
Spitzer 2012
Treatment
Comparison
Scale
Duration
Treatment Comparison
Significant
in original
study††
14 wk
66 (27.2)
No
Testim 1%, gel,
50–150 mg/d
+ sildenafil
Placebo +
sildenafil
QOL-MED
69 (27.2)
Zhang 2012
Andriol, oral,
120-160 mg/d
Placebo
AMS score¶
6 mo
32.9 (9.2)
52.1 (10.3)
Yes**
Aversa 2010
Testosterone
undecanoate,
oral, 160 mg/d
Placebo
AMS score
6 mo
36 (3)
36 (4)
No
Kenny 2010
Androgel 1%,
gel, 5 mg/d
Placebo
IPSS, QoL
domain¶
12 mo
2.5 (1.3)
Morales 2009
Andriol, oral,
160 mg/d
Placebo
AMS score
16 wk
34.3 (13.3) 37.7 (10.7)
No
Emmelot-Vonk
2009
Andriol, oral,
160 mg/d
Placebo
Questions on
6 mo
Life Satisfaction
Modules,
health domain¶
75.9 (28.7) 77.7 (13.7)
No
Shores 2009
Androgel 1%,
gel, 75 mg/d
Placebo
Q-LES-Q¶
12 wk
50.1 (11.1) 53.4 (13.7)
No
Orengo 2005
Androgel 1%,
gel, 50 mg/d
Placebo
Q-LES-Q
12 wk
44 (7.1)
No
3 (1.5)
45.6 (12.5)
No**
SMD (SD)
Results in AMS
score units,
mean (SD)
0.11 (1.97)
1.05 (18.87)
–1.96 (1.98)
–18.78 (18.97)
–0.03 (2.02)
–0.29 (19.35)
–0.33 (1.96)
–3.16 (18.78)
–0.08 (1.41)
–0.77 (13.51)
0.26 (2.00)
2.49 (19.16)
0.16 (2.04)
1.53 (19.54)
Note: AMS = Aging Male Symptom rating scale, IPSS = International Prostate Symptom Score, NR = not reported, QoL = quality of life, QoL-MED = Quality of Life Specific to Male
Erection Difficulties, Q-LES-Q = Quality of Life Enjoyment and Satisfaction Questionnaire.
¶More than one scale reported.
** Calculated on the basis of reported data.
††Between groups after treatment.
12
Some of the included studies used more than one scale to evaluate quality of life. Summary scales were
chosen over individual subscales if possible. For example, the study by Zhang and colleagues (24) used
the Aging Male Symptom rating scale as well as the SF-12 scale to evaluate quality of life; however, they
did not report an overall score for SF-12 (reported separate scores for the physical and mental
subscales), and the AMS is a disease specific health related quality of life scale in aging men.
Erectile dysfunction
Ten studies (3, 6, 22, 23, 25, 26, 32, 33, 35, 36) assessed the efficacy of testosterone on erectile
dysfunction. Most used the International Index of Erectile Function (IIEF; also known as IIEF-15) scale, or
a shortened version (IIEF-5). IIEF has 5 domains: erectile function, orgasmic function, sexual desire,
intercourse satisfaction, and overall satisfaction. Four studies were excluded from this analysis. Shabsigh
and colleagues used a dichotomous outcome of response v. no response(3), Emmelot-Vonk and
colleagues reported the number of nocturnal erections per 14-day period (36), Dobs and colleagues (35)
assessed nocturnal erectile activity, and Boyanov and colleagues (26) assessed erectile function using
the IIEF scale but reported the outcome using a 4-point Likert scale. The results were available for 4
treatments and reported in the units of the IIEF (erectile dysfunction domain) in Exhibit 4. No significant
improvements in erectile dysfunction were identified. However, two studies found a significant
difference improvement in erectile dysfunction (Cavallini (55) - testosterone undecanoate, oral,
160 mg/day; and Chiang (14) - Androgel 1%, gel, 50 mg/d) compared to placebo. The original data are
shown in Exhibit 6.
Exhibit 6: Summary of studies that reported erectile dysfunction
After treatment,
mean (SD)
Study
Spitzer 2012
Treatment
Testim 1%, gel,
50–150 mg/d +
sildenafil
Comparis
on
Placebo
Scale
Duration
Treatment Comparison
IIEF, EF
domain
14 wk
21 (8.54)
19 (8.54)
Significant
in original
study*
SMD (SD)
Results in IIEF
score units
(erectile function
domain), mean
(SD)
0.24 (1.97)
1.40 (11.41)
0.63 (1.42)
3.62 (8.18)
-0.02 (1.99)
–0.13 (11.48)
0.57 (1.44)
3.29 (8.31)
No
Aversa 2010
Testosterone
Placebo
undecanoate, oral,
160 mg/d
IIEF-5
6 mo
18 (3)
19 (4)
No†
Cavallini 2004
Testosterone
Placebo
undecanoate, oral,
160 mg/day
IIEF, EF
domain
6 mo
16 (5.75)
9 (4)
Yes†
Morales 2009
Andriol, oral,
160 mg/d
Placebo
IIEF, EF
domain
16 wk
11.1 (7.7)
11.3 (9.1)
No
Chiang 2009
Androgel 1%, gel,
50 mg/d
Placebo
IIEF-5
3 mo
16.9 (5.1)
12.2 (7)
Yes†
Chiang 2007
Androgel 1%, gel,
50 mg/d
Placebo
IIEF, EF
domain
3 mo
21.6 (6.8)
18.1 (10.7)
No†
Note: EF = erectile function, SD = standard deviation, SE = standard error, SMD = standardized mean difference, AMS = Aging Male Symptom, IIEF = International Index of Erectile
Function.
*Between groups after treatment.
† Calculated on the basis of reported data.
13
Libido
Nine studies (6, 15, 20, 22, 23, 26, 27, 32, 36) assessed the efficacy of testosterone on libido. Of these,
two used the sexual desire domain of the IIEF scale. Two studies could not be included in the analysis:
one used a binary outcome (e.g., “less than once a week” v. “more than once a week” for desire of
sexual contact) and one did not report sufficient data for analysis. The results were available for 7
treatments and reported in the units of the IIEF sexual desire domain in Exhibit 4. No significant
improvements in libido were identified. However, three studies found a significant difference in libido;
two found a deterioration in libido in the TRT group (Chiang (14) - Androgel 1%, gel, 50 mg/d; Steidle
(44) - Testim 1%,gel, 100 mg/d) and one study involving type II diabetic men found an improvement
(Boyanov (11) - Andriol, oral, 120 mg/d) compared to placebo. The original data are shown in Exhibit 7.
Exhibit 7: Summary of studies that reported libido
After treatment,
mean (SD)
Study
Spitzer 2012
Treatment
Comparison
Scale
Duration Treatment
Comparison
Testim 1%, gel,
50–150 mg/d +
sildenafil
Placebo +
sildenafil
MSHQ, sexual 14 wk
desire domain
10.5 (3.95)
Andriol, oral,
160 mg/d
Placebo
IIEF, sexual
desire
domain
4 mo
5 (2.0)
Androgel 1%,
gel, 50 mg/d
Placebo
IIEF, sexual
desire
domain
3 mo
Steidle 2003, a
Androderm,
patch, 5 mg/d
Placebo
PDQ
3 mo
• 1.6 (1.4)†
1.6 (1.4)†
Steidle 2003, b
Testim 1%, gel,
50 mg/d
Placebo
PDQ
3 mo
• 1.8 (1.4)†
1.6 (1.4)†
No
Steidle 2003, c
Testim 1%,gel,
100 mg/d
Placebo
3 mo
• 1.4 (1.4)†
1.6 (1.4)†
Yes
Boyanov 2003
Andriol, oral,
120 mg/d
Placebo
Morales 2009
Chiang 2009
PDQ
Subscale of
3 mo
PADAM
questionnaire
3.6 (1.6)†
10 (2.89)
Significant
in original
study*
6.1 (2.10)
6.3 (2.4)†
2.125 (0.61) 1.675 (1.25)
SMD (SD)
Results in IIEF
score units
(sexual desire
domain), mean
(SD)
No
0.15 (2.43)
0.28 (5.24)
–0.53 (2.43)
–1.11 (5.18)
–0.77 (1.98)
–1.65 (4.30)
–0.45 (1.98)
–0.94 (4.26)
–0.06 (2.31)
–0.14 (5.03)
No
Yes
No
0.28 (3.35)
0.51 (7.31)
Yes
-0.53 (2.43)
0.97 (5.22)
Note: AMS = Aging Male Symptom, IIEF = International Index of Erectile Function, MSHQ = Male Sexual Health Questionnaire, PADAM = Partial Androgen Deficiency of Aging
Men, PDQ = Psychosexual Daily Questionnaire, SD = standard deviation, SE = standard error, SMD = standardized mean difference.
*Between groups after treatment, unless stated otherwise.
†Calculated based on change score and before treatment values.
14
Depression
Seven studies (10, 13, 17, 22, 24, 30, 35) assessed the efficacy of testosterone on depression. Two
studies enrolled men with depression at baseline (10, 13), and one enrolled patients with HIV (17). The
results were available for 7 treatments and reported in the units of the Beck Depression Inventory in
Exhibit 4. No significant effects on depression were identified. However, the single study by Zhang and
colleagues (24) found a significant improvement in depression for Andriol, oral, 120–160 mg/d
compared to placebo; the original data are shown in Exhibit 8.
Exhibit 8: Summary of studies that reported depression
After treatment, mean
(SD)
Study
Zhang 2012
Treatment
Comparison
Scale
Duration Treatment
Comparison
HADS,
depression
subscale
6 mo
4.29 (0.7)
Significant
in original
study††
Andriol, oral,
120-160
mg/d
Placebo
Shores 2009
Androgel 1%,
gel, 75 mg/d
Placebo
HAM-D
12 wk
8.4 (5)
11.4 (4.4)
No§
Orengo 2005
Androgel 1%,
gel,
50 mg/d
Placebo
HAM-D
12 wk
9.4 (4.4)
9.4 (9.7)
No
Amory 2004
Dobs 1999
Grinspoon 199
Cavallini 2004
Testosterone Placebo
enanthate, IM,
200 mg/2wk
Beck
Depression
Inventory
4 mo*
Androderm,
patch, 5 mg/d
Placebo
Beck
Depression
Inventory
24 wk
Testosterone
enanthate,
IM,
300 mg/3wk
Placebo
Beck
Depression
Inventory
6 mo
Testosterone
undecanoate,
oral, 160
mg/day
Placebo
Hamilton
Depression
and
Melancholia
Scale
6 mo
2.39 (0.3)
3.2 (0.6)
5.9 (6)†
9.2 (1.4)
5 (0.75)‡
4.8 (1)
4.5 (4.2)†
10.8 (1.6)
7 (0.75)‡
SMD (SD)
Results in Beck
score units,
mean (SD)
–3.49 (2.91)
–4.08 (3.40)
–0.59 (2.93)
–0.69 (3.43)
0.02 (2.91)
0.02 (3.41)
–1.96 (2.87)
–2.29 (3.36)†
–1.72 (4.06)
–2.01 (4.75)†
–1.03 (2.89)
–1.20 (3.38)
–2.65 (2.90)
–3.10 (3.39)
Yes
No
No
No§
No
Note: HADS = Hospital Anxiety and Depression Scale, HAM-D = Hamilton Rating Scale for Depression, SD = standard deviation, SE = standard error, SMD = standardized mean
difference.
*Data for 36 mo were also available. The 4-month time point was chosen for consistency with the other studies.
†Calculated using change score and before treatment data.
‡Calculated based on median and range.
††Between groups after treatment.
§Calculated on the basis of reported data (note: in Shores 2009, when adjusted for age significance is found but there is no strong justification for the covariate analysis. .
15
Other efficacy outcomes were considered, but the data on these outcomes were limited:
Fractures
One study assessed fractures as an efficacy outcome (37). Wang and colleagues included men with a
serum testosterone level less than 300 ng/dL at baseline and osteoporosis (defined as a bone mineral
density of 2.5 SD lower than the peak mean of the same gender) and excluded men with the presence or
history of vertebral, hip, or wrist fractures or other metabolic bone diseases (n = 186). None of the
included men were taking a testosterone product at baseline. Wang and colleagues (37) randomized
men (mean age 68.2, SD 5.2 yr) to Andriol (20 mg/d, n = 62; 40 mg/day, n = 62) and 62 men to placebo
for 24 months. The mean testosterone levels among the groups were similar at baseline (mean total
testosterone level less than 220 ng/dl in all groups). At the end of the 24 month study period, no
vertebral fractures were reported in any group.
One hip fracture was reported as an adverse event in the placebo group in the study by Brokenbrough
and colleagues (12). This study included 40 men with end-stage renal disease randomized to Testim 1%
gel (100 mg/d; n = 19, mean age 58.9 [SD 14.9] yr) or placebo (n = 21, mean age 53.0 [SD 17.2]).
Activities of daily living
None of the included studies investigated activities of daily living as an outcome.
Comparisons among the testosterone replacement therapies
Summaries of the head-to-head comparisons among the Health Canada-approved doses of testosterone
replacement therapies are presented in Appendix C for serum testosterone level at 3 months, quality of
life, erectile dysfunction, libido and depression. In particular, the results for the serum testosterone
level are provided in Exhibit 9. In general:
•
•
•
Androgel 1%, gel, 100 mg/d was associated with more favourable serum testosterone levels at 3
months than the other testosterone replacement therapies.
Andriol, oral, 120 mg/d was associated with less favourable serum testosterone levels at 3
months than the other testosterone replacement therapies.
No significant differences among the testosterone replacement therapies for quality of life,
erectile dysfunction, libido, and depression were identified.
16
Exhibit 9: Head-to-head comparisons of the testosterone treatments on serum testosterone level at
3 months*
1
2
3
4
5
6
7
8
9
10
11
1
2
3
4
5
6
7
8
9
10
11
* For serum testosterone level at 3 months:
•
The green block indicates that the ‘row’ treatment is significantly better than the ‘column’ treatment.
•
The red block indicates that the ‘row’ treatment is significantly worse than the ‘column’ treatment.
•
The grey block indicates that there is no significant difference between the ‘row’ and ‘column’ treatment.
Treatments:
1. Androderm, patch, 5 mg/d
2. Androgel 1%, gel, 50 mg/d
4. Testim 1%, gel, 50–150 mg/d + sildenafil
5. Testim 1%, gel, 50 mg
7. Andriol, oral, 120 mg/d
8. Delatestryl, IM, 200 mg/2wk
9. Testosterone enanthate, IM, 100 mg/wk
10. Testosterone enanthate, IM, 200 mg/2wk
11. Testosterone cypionate, IM, 200 mg/2wk
Safety
Cardiovascular death
In total, two trials reported cardiovascular death (9, 12). Based on the comprehensive reporting of
withdrawals and adverse events, we inferred that no cardiovascular deaths occurred in three additional
trials (10, 26, 30). Network meta-analysis was not possible for this outcome because the events were
rare and the study treatments too variable. Meta-analysis was performed by pooling all testosterone
treatments as a group and comparing outcomes among testosterone-treated participants versus
placebo-treated participants. No events were reported in the placebo group, and a total of 4
cardiovascular deaths were reported in the treatment groups of two studies (9, 12). The studies by
Brockenbrough and colleagues (12) and Basaria and colleagues (9) both involved treatment with Testim
1% gel (Brockenbrough: 50 mg/d; Basaria: 100 mg/d). Based on these two studies, the odds of
cardiovascular death are 8.62 times higher in the testosterone group than in the control group (OR 8.62,
95% CI 1.17–63.77) (Exhibit 10).
17
No events were reported in the trials by Boyanov and colleagues (26); Andriol, 120 mg/d) or Amory and
colleagues (30); testosterone enanthate, 200 mg/2wk).
Exhibit 10: Cardiovascular death: odds ratios of any testosterone compared to placebo
Study or Subgroup
Brockenbrough 2006
Boyanov 2003
Amory 2004
Shores 2009
Basaria 2010
TRT
Placebo
Peto Odds Ratio
Events Total Events Total Weight Peto, Fixed, 95% CI Year
3
0
0
0
1
Total (95% CI)
19
24
24
17
106
0
0
0
0
0
190
21 74.0%
24
24
16
103 26.0%
9.20 [0.90, 94.21]
Not estimable
Not estimable
Not estimable
7.18 [0.14, 362.14]
188 100.0%
8.62 [1.17, 63.77]
Peto Odds Ratio
Peto, Fixed, 95% CI
2003
2004
2009
2010
Total events
4
0
Heterogeneity: Chi² = 0.01, df = 1 (P = 0.92); I² = 0%
Test for overall effect: Z = 2.11 (P = 0.03)
0.01
0.1
1
Placebo TRT
10
100
Of the five trials included for this outcome, three compared testosterone gel and placebo: Basaria and
colleagues (9), Testim 1% (100 mg/d); Brockenbrough and colleagues (12), Testim 1% (50 mg/d); and
Shores and colleagues (10), Androgel 1% (75 mg/d). The grouping of treatments by route of
administration (gel v. placebo) yielded the same OR as reported above for the comparison of “any
testosterone” v. placebo (Exhibit 11).
Exhibit 11: Cardiovascular death: odds ratios of testosterone gel compared to placebo
Study or Subgroup
Brockenbrough 2006
Shores 2009
Basaria 2010
TRT gel
Placebo
Peto Odds Ratio
3
0
1
Total (95% CI)
19
17
106
142
0
0
0
21 74.0%
16
103 26.0%
9.20 [0.90, 94.21]
Not estimable 2009
7.18 [0.14, 362.14] 2010
140 100.0%
8.62 [1.17, 63.77]
Total events
4
0
Peto Odds Ratio
Peto, Fixed, 95% CI
0.01
0.1
1
10
Placebo TRT gel
100
Myocardial infarction
Four studies reported myocardial infarction (8, 9, 25, 30). Of these, myocardial infarction was explicitly
reported in three trials (8, 9, 25) and was inferred in one (based on reporting of withdrawals and
adverse events (30). One myocardial infarction was reported in the placebo group in the study by Aversa
and colleagues (25); however, we were unable to include this event in the subsequent analysis for the
following reason: Aversa and colleagues used a cross-over trial design, in which participants in each of
18
the two treatment groups (testosterone undecanoate, oral, 160 mg/d; testosterone undecanoate,
intramuscular injection, 1000 mg/12 wk) received treatment for 6 months, then switched to the
opposite treatment. Injectable testosterone undecanoate is not approved by Health Canada.
Participants in the control group received placebo for the full 12 month period. Because of the crossover design, we extracted data for only the first 6 month period. However, for the one myocardial
infarction that occurred in the placebo group, it was not reported whether the event occurred in the
first or second 6 month period.
Network meta-analysis was not possible for this outcome because the events were rare and the study
treatments too variable. We performed two meta-analyses for this outcome: any testosterone v.
placebo, and testosterone gel v. placebo.
First, meta-analysis was performed by comparing all testosterone treatments to placebo. Three studies
were included in the analysis (8, 9, 30). The study by Kenny and colleagues (8) involved Androgel 1% (5
mg/d), Basaria and colleagues (9) used Testim 1% gel (100 mg/d), and Amory and colleagues (30) used
testosterone enanthate (IM, 200 mg/2wk). Overall, there were two events in the testosterone group
and one event in the placebo group, resulting in an odds ratio of 1.85 (95%CI 0.19–17.86) (Exhibit 12).
Exhibit 12: Myocardial infarction: odds ratios of any testosterone compared to placebo
Study or Subgroup
Amory 2004
Basaria 2010
Kenny 2010
Total (95% CI)
TRT
Placebo
Peto Odds Ratio
Events Total Events Total Weight Peto, Fixed, 95% CI
0
2
0
24
106
69
199
0
0
1
24
103 66.6%
62 33.4%
Not estimable
7.25 [0.45, 116.75]
0.12 [0.00, 6.13]
189 100.0%
1.85 [0.19, 17.86]
Total events
2
1
Peto Odds Ratio
Peto, Fixed, 95% CI
0.01
0.1
1
Placebo TRT
10
100
Next, a meta-analysis was performed for the two studies that compared treatment with testosterone gel
versus placebo. Two studies were included in this analysis (8, 9).The testosterone gel used in the study
by Basaria and colleagues (9) was Testim 1% (100 mg/d), while the testosterone gel used in the study by
Kenny and colleagues (8) was Androgel 1% (5 mg/d). Myocardial infarctions were rare (2 in the gel group
and 1 in the placebo group) in these two studies, resulting in an overall OR of 1.85 (95% CI 0.19–17.86)
(Exhibit 13).
19
Exhibit 13: Myocardial infarction: odds ratios of testosterone gel compared to placebo
Study or Subgroup
Basaria 2010
Kenny 2010
Total (95% CI)
TRT
Placebo
Events Total Events Total Weight
2
0
106
69
175
0
1
Peto Odds Ratio
Peto, Fixed, 95% CI
103 66.6%
62 33.4%
7.25 [0.45, 116.75]
0.12 [0.00, 6.13]
165 100.0%
1.85 [0.19, 17.86]
Total events
2
1
Peto Odds Ratio
Peto, Fixed, 95% CI
0.01
0.1
1
Placebo TRT
10
100
The trial by Basaria and colleagues enrolled men who were aged 65 years and older (mean age 74 yr)
and had mobility limitations (9). The mean baseline total testosterone level in this trial was 243 ng/dl;
men in this trial received testosterone or placebo for 6 months. Kenny and colleagues included men
aged 60 years and older with low bone mass and physical frailty (8). The mean baseline testosterone
level in this study was 398.0 (standard deviation (SD) 185.9) ng/dL; men in this study received
testosterone or placebo for 24 months.
Although the mean age was similar in both trials, men in the treatment arms of the trial by Basaria and
colleagues (9) had a higher prevalence of hypertension (85% v. 15% of participants), diabetes (24% v.
8%), coronary artery disease (53% v. 16%). In total, 45% of participants in the trial by Basaria and
colleagues (9) were obese (BMI > 30), and 63% had hyperlipidemia (data for these comorbidities were
not reported by Kenny et al.(8)).
Stroke
Four trials were identified for which stroke was reported (9, 12, 18) or inferred (30). Network metaanalysis was not possible for this outcome because the events were rare and the study treatments were
too variable. Meta-analysis was performed for any testosterone treatment versus placebo and for
testosterone gel versus placebo.
In the meta-analysis of any testosterone treatment compared to placebo, there was one stroke in the
testosterone group and two in the placebo group, resulting in an odds ratio of 0.50 (95% CI 0.05–4.85)
(Exhibit 14). The one stroke in the testosterone group occurred in the trial by Basaria and colleagues (9),
which compared the use of Testim 1% (100 mg/d) to placebo in elderly community-dwelling men with
limited mobility (mean age 74 yr). Brockenbrough and colleagues (12) also compared the use of Testim
1% (100 mg/d), while participants in the trial by Sih and colleagues (18) received testosterone cypionate
(IM injection, 200 mg/2wk). Brockenbrough and colleagues (12) enrolled men aged ≥ 18 years with
hemodialysis-dependent end-stage renal disease (mean age: treatment: 59 yr; placebo: 53 yr), while Sih
20
and colleagues (18) enrolled community-dwelling older men ≥ 50 years (mean age: treatment: mean 65
[SD 7] yr; placebo: 68 (7) yr).
Exhibit 14: Stroke: odds ratios of any testosterone compared to placebo
Study or Subgroup
TRT
Placebo
Peto Odds Ratio
Brockenbrough 2006
Sih 1997
Amory 2004
Basaria 2010
0
0
0
1
Total (95% CI)
19
17
24
106
1
1
0
0
21 33.3%
15 33.3%
24
103 33.4%
166
163 100.0%
Peto Odds Ratio
Peto, Fixed, 95% CI
0.15 [0.00, 7.54]
0.12 [0.00, 6.02] 1997
Not estimable 2004
7.18 [0.14, 362.14] 2010
0.50 [0.05, 4.85]
Total events
1
2
0.01
0.1
1
Placebo TRT
10
100
Two trials involved testosterone gel (Testim 1% gel, 100 mg/d) as the treatment (9, 12). In total, there
was one event each in the Testim 1% gel group and one event in the placebo group, with results in the 2
included studies going in opposite directions, giving an overall OR of 1.04 (95% CI 0.06 – 16.60) (Exhibit
15).
Exhibit 15: Stroke: odds ratios of testosterone gel compared to placebo
Study or Subgroup
Testim 1% Gel
Placebo
Peto Odds Ratio
Brockenbrough 2006
Basaria 2010
Total (95% CI)
0
1
19
106
1
0
125
Total events
1
1
21
103
49.9%
50.1%
124 100.0%
Peto Odds Ratio
Peto, Fixed, 95% CI
0.15 [0.00, 7.54] 2006
7.18 [0.14, 362.14] 2010
1.04 [0.06, 16.60]
0.01
0.1
1
10
100
Favours Testim 1% Gel Favours placebo
Newly diagnosed disease
a)
Prostate cancer
In total, 8 studies (8, 9, 11, 15, 20, 30, 35, 36) reported prostate cancer. Zero events were inferred for
one additional study (40).
Network meta-analysis was not possible for this outcome because the events were rare and the study
21
treatments were too variable. Meta-analysis was performed for any testosterone treatment versus
control, for testosterone gel versus placebo, and for testosterone IM injection versus placebo.
Seven studies were included in the meta-analysis of any testosterone treatment versus placebo (8, 9, 11,
15, 30, 36, 40). Two studies were excluded from this analysis because they did not involve a placebo or
no treatment group (20, 35). Overall, the odds of prostate cancer were slightly higher in the
testosterone group (OR 1.17, 95% CI 0.42–3.27); however, this increase was not statistically significant
(Exhibit 16).
Exhibit 16: Prostate Cancer: odds ratios of any testosterone compared to placebo
Next, meta-analysis was performed by grouping studies by route of administration (testosterone gel v.
placebo; IM v. placebo). Four studies involved treatment with testosterone gel: testosterone gel (brand
not reported), 125 mg/d (40); Testim 1% gel, 50 mg/d, (15); Androgel 1%, 5 mg/d (8); Testim 1%, gel,
100 mg/d (9). Of these studies, events were reported by Kenny and colleagues (8) (one in each of the
treatment and placebo groups) and by Basaria and colleagues (9) (one event in the treatment group),
resulting in an OR of 1.80 (95% CI 0.19–17.48) (Exhibit 17).
Exhibit 17: Prostate Cancer: odds ratios of testosterone gel compared to placebo
TRT gel
Study or Subgroup
Placebo
Peto Odds Ratio
Basaria 2010
1
106
0
103
33.6%
7.18 [0.14, 362.14]
Kenny 2010
1
69
1
62
66.4%
0.90 [0.06, 14.56]
Simon 2001
0
6
0
6
Not estimable
Steidle 2003
0
205
0
99
Not estimable
Total (95% CI)
Total events
386
2
270
Peto, Fixed, 95% CI
1.80 [0.19, 17.48]
1
100.0%
Peto Odds Ratio
Peto, Fixed, 95% CI
0.01
0.1
1
Placebo
10
100
TRT gel
22
Two studies involved treatment with intramuscular injection of testosterone: testosterone enanthate,
200 mg/2 wk (30); and Delatestryl, 150 mg/2wk (11). In total, there were 4 events in the testosterone
IM group and 5 in the placebo group, resulting in an overall OR of 0.78 (95% CI 0.20–3.08) (Exhibit 18).
Exhibit 18: Prostate Cancer: odds ratios of IM testosterone compared to placebo
IM TRT
Study or Subgroup
Placebo
Peto Odds Ratio
Amory 2004
2
24
1
24
35.1%
2.01 [0.20, 20.27]
Marks 2006
2
22
4
22
64.9%
0.47 [0.09, 2.58]
46 100.0%
0.78 [0.20, 3.08]
Total (95% CI)
Total events
46
4
Peto Odds Ratio
Peto, Fixed, 95% CI
Peto, Fixed, 95% CI
5
0.01
0.1
1
Placebo IM TRT
10
100
Of the remaining three studies not included in the meta-analysis, one study compared placebo to
Andriol (160 mg/d; (36)). There were two cases of prostate cancer in the placebo group (n = 117) and
zero events in the treatment arm (n = 120). Another study compared Androderm (5 mg/d) to Androgel
1% (50 mg/d or 100 mg/d; (20)). In this study, there was one case of prostate cancer among 78
participants in the Androgel 1% 100 mg/d group and no cases in the Androderm group (n = 76) or the
Androgel 1% 50 mg/d group (n = 73). The third study compared Androderm (5 mg/d) and Delatestryl
(200 mg/2wk; (35)). There was one case of prostate cancer (n = 33) in the Androderm group and 2 cases
(n = 33) in the Delatestryl group.
b)
Diabetes
No studies reported newly diagnosed diabetes.
c)
Heart disease
One study reported the development of newly diagnosed heart disease during the study period (8).This
trial enrolled men aged 60 and older with total testosterone levels of less than 350 ng/dl and low bone
mineral density and physical frailty. In total, 131 participants (mean age 77.1 [SD 7.6 years]) were
randomized to receive Androgel (5 mg/d) or placebo for at least 16 months. At baseline, 30% of
23
participants had hypertension. Two cases were reported in the treatment group (2/69) and four cases
were reported in the placebo group (4/62).
Serious adverse events
Seven trials (5, 6, 9, 10, 25, 36, 40) reported serious adverse events (SAE; as defined by the authors). Of
these, three trials reported data that was suitable for meta-analysis (6, 9, 40). Each of these trials
involved testosterone gel as the intervention: testosterone gel ([brand not specified], 125 mg/d) (40),
Testim 1% gel (100 mg/d (9); or Testim 1% gel (50–150 mg/d + sildenafil (6). Participants in the Testim
and placebo groups in the trial by Spitzer and colleagues (6) also received sildenafil. In the treatment
group, 76% of men received 100 mg sildenafil, 23% received 50 mg and 1% received 35 mg. In the
placebo group, 76% received 100 mg and 24% received 50 mg. Sildenafil was taken “as needed” in both
groups.
The meta-analysis of testosterone versus placebo yielded an overall OR of 1.61 (95% CI 0.77–3.36)
(Exhibit 19).
Exhibit 19: Serious Adverse Events: odds ratios of testosterone gel compared to placebo
Study or Subgroup
Simon 2001
Shores 2009
Basaria 2010
Spitzer 2012
Total (95% CI)
TRT
Placebo
1
0
16
2
6
17
106
70
199
0
0
8
4
Peto Odds Ratio
Peto, Fixed, 95% CI Year
6
3.6%
16
103 75.9%
70 20.6%
7.39 [0.15, 372.38]
Not estimable
2.05 [0.88, 4.79]
0.50 [0.10, 2.56]
195 100.0%
1.61 [0.77, 3.36]
19
12
Total events
Peto Odds Ratio
Peto, Fixed, 95% CI
2001
2009
2010
2012
0.01
0.1
1
Placebo TRT
10
100
Of the remaining three studies, two studies were not included in the analysis because they reported the
number of events (instead of the number of participants who had at least one event) (25, 36). Another
study not included in the meta-analysis because it used a factorial design but did not report outcomes
by treatment group (5). Hildreth and colleagues (5) randomized participants to one of the following
arms: 1) placebo and an exercise program; 2) testosterone therapy and an exercise program; 3) placebo
and no exercise program; 4) testosterone therapy and no exercise program (5). However, the data for
SAE were reported for participants who received testosterone therapy versus those who received
placebo, regardless of the exercise component. This made it difficult to ascertain to which group the
SAEs were attributable.
In the study by Hildreth and colleagues (5), 123 events were experienced by 96 participants who
received the Androgel 1%, compared to 64 events experienced by 47 participants in the placebo group.
24
In the study by Aversa and colleagues (25) there were no events reported in either group (testosterone
undecanoate (160 mg/d): n = 10; placebo: n = 10).
Emmelot-Vonk and colleagues (36) reported the occurrence of 5 events among 113 participants who
received oral testosterone (Andriol, 160 mg/d) compared with 10 events among 110 participants in the
placebo group.
Erythrocytosis
Of the included studies, only three reported erythrocytosis (either occurrence or lack of occurrence). In
all three studies, the type of testosterone therapy used was intramuscular testosterone enanthate (2
studies) and testosterone undecanoate (3 studies).
In two studies (11, 25), one patient from each study withdrew from their respective intramuscular
testosterone treatment group (testosterone undecanoate and testosterone enanthate) as a result of the
onset of erythrocytosis. In the third study (14), the authors advised that none of the five patients
assigned to the either of the two study groups (placebo or intramuscular testosterone enanthate)
developed “polycythemia or hyperlipidemia”.
Skin reactions
Of the included RCTs, ten reported treatment-related skin reactions (10, 12, 15, 20, 27, 29, 32, 33, 35,
36) (Appendix D).In general, all events were related to the use of three types of testosterone (gel, patch,
oral) or placebo treatment.
Four studies, (15, 20, 27, 29) described the use of “skin irritation assessment” scores to characterize the
type of skin reaction experienced by participants. Three of these studies used the following scale: 0, no
erythema; 1, minimal erythema; 2, moderate erythema with sharply defined borders; 3, intense
erythema with or without edema; 4, intense erythema with edema and blistering to assist with this
characterization. The fourth study (29) used a “Modified Marzulli and Maibach scale” to complete
similar skin-reaction assessments.
Of the studies involved orally administered testosterone therapy, only one reported adverse skin
reactions among participants. In this study, the same number of participants in each of treatment group
(Andriol, placebo) reported undisclosed “skin problems.”
Overall, skin-related adverse effects ranged from mild skin irritation to rashes and from allergic contact
dermatitis and moderate skin erythema to intense edema and blistering. Three studies reported that
patients experienced blistering as a result of testosterone treatment. Of these, two were associated
with testosterone patches (Androderm) and one was associated with the application of testosterone gel
to the skin (Androgel 1%).
25
Non-Randomized Studies
A total of 24 unique non-randomized studies (25 reports) included at least on Health Canada–approved
testosterone treatment (Exhibit 20, Appendix E). Of these, 16 did not report an outcome of interest (4156). Eight studies included at least one outcome of interest and are summarized in Appendix F.
The most frequently reported safety outcome was prostate cancer; however, the reporting was
generally poor.
Rhoden and colleagues (57) reported one case of prostate cancer in a comparison of intramuscular
injection of testosterone (n = 33; dose not reported) and testosterone gel (n = 25; Androgel 1% or
Testim 1%, doses not reported). The group in which the prostate cancer occurred was not reported.
Guay and colleagues (58) reported a retrospective cohort study involving treatment with testosterone
enanthate (200–300 mg/2–3 wk), non-scrotal testosterone patch (5 mg/d), and clomiphene citrate.
Three cases of prostate cancer were reported; however, to which group the affected patients belonged
was not reported. Prostate cancer was also reported in the study by Hajjar and colleagues (59);
however, they used a composite outcome of “benign prostatic hyperplasia/prostate cancer”. Although
there were multiple events in each group, we cannot determine which of these events were prostate
cancer and which were benign. Three cases of prostate cancer also occurred in the study by Dean and
colleagues (60), which compared Testim 1% gel at two doses (50 mg/d v. 100 mg/d). The group in which
the three cases occurred was not reported.
Shores and colleagues (61) reported 7 cases of prostate cancer in the testosterone treatment group (n =
398 men) and 13 cases in the “no treatment” group (n = 633). The testosterone products included in this
study were injectables, patch, and gel; however, the brands and doses were not specified.
Hajjar and colleagues (59) performed a retrospective analysis of 45 elderly men taking testosterone
replacement therapy and 27 hypogonadal men not taking testosterone. The products used were
testosterone enanthate or cypionate (200 mg/2–3 wk). The authors report many adverse events
including myocardial infarction, stroke, newly diagnosed diabetes and erythrocytosis (Exhibit 10);
however, the data were poorly reported, and the number of people that their analyses are based on is
not clear.
Vigen and colleagues (62) performed a retrospective cohort study of men with low testosterone (< 300
ng/dl [10.4 nmol/L]) who had undergone coronary angiography between 2005 and 2011 at a Veterans
Affairs facility in the United States (n = 8709). Of the included men, 1223 began testosterone
replacement therapy following angiography. A total of 1710 events (composite of all-cause mortality,
myocardial infarction, ischemic stroke) occurred during follow-up among those taking a testosterone
product, compared to 681 events among 7486 patients not taking testosterone, giving an absolute risk
difference of 5.8% (95% CI –1.4% to 13.1%) three years after coronary angiography. Although the
number of events in the group not taking testosterone is higher than in the TRT group, the patients not
26
taking testosterone were followed for longer (thus more time at risk of an event). After adjustment for
the presence of coronary artery disease at baseline, the risk of an event was greater among men taking
testosterone (hazard ratio 1.29, 95% CI 1.04–1.58) (62).
Exhibit 20: Included non-randomized studies that reported at least one safety outcome of interest
Study
Treatment (no. in group)
Outcome reported
Data
Comments
Blick 2013
• Androgel 1%, gel, 50 mg/d
(n = 92)
• Testim 1%, gel, 50 mg/d
(n = 75)
• Erythrocytosis
• Prostate cancer
Erythrocytosis
• Androgel: 0/92
• Testim: 0/75
Prostate cancer
• Androgel: 0/92
• Testim: 0/75
Skin reactions were assessed but not
reported
Hajjar 1997
• No treatment (n = 27)
• Testosterone enanthate or
cypionate, IM, 200mg/2-3
wk (n = 45)
• Myocardial infarction
• Stroke
• Erythrocytosis
• Diabetes
• Skin reactions
Myocardial infarction
• No treatment: 0/23
• TRT: 1/26
Stroke
• TRT: 1/26
Diabetes
• TRT: 1/26
Erythrocytosis*
• TRT: 11/45
Data not clearly provided. Safety
outcomes were reported based on a
subset of people assigned to each group,
and it is not clear why the other patients
were omitted.
Prostate cancer was reported as “benign
prostatic hypertrophy/prostate cancer”;
the number of patients with prostate
cancer was not reported (6/23 in control
group; 2/26 in TRT group)
Dean 2005
• Prostate cancer
• Skin reactions
Three prostate cancer events
occurred, but not reported to
which treatment group the
patients belonged
Total number of men in each group not
reported (total n = 371)
Guay 2000
• Testosterone enanthate,
IM, 200-300 mg/2-3 wk
(n = 25)
• Testosterone, patch (nonscrotal), 5 mg/d (n = 16)
• Clomiphene citrate, oral,
50 mg/3x per wk (n = 49)
• Prostate cancer
Three cases of prostate cancer
reported; however, not reported
to which treatment group the
patients belonged
"Of the overall group of 90 patients, 10
were referred for ultrasonography and
prostate biopsy. In two patients,
biopsy specimens were positive for
adenocarcinoma. In a third patient,
biopsy studies were repeated because of
an equivocal result, and the presence of
prostate carcinoma was ultimately
confirmed “
Vigen 2013
• TRT (n = 1223)
• Cardiovascular events†
Absolute difference for
cardiovascular events† in TRT
group, 3 years after coronary
angiography: 5.8% (–1.4% to
13.1% (19.9% in no TRT group,
25.7% in TRT group)
Entry into cohort was based on filling a
prescription for TRT (patch, gel,
injectable; brands not specified). Data
reported as TRT v. no TRT (not by type of
TRT). Raw data provided for MI, stroke
and all-cause death, but length of
follow-up differed by group.
Shores 2012
• TRT (n = 398)
• Prostate cancer
• No treatment: 13/633 men
• TRT: 7/398 men
Data reported as TRT v. no TRT (not by
type of TRT). TRTs included injectable,
patch, or gel (brands not specified)
Rhoden 2006
• Testosterone, IM (n = 33)
• Androgel 1% or Testim 1%
(n = 25)
• Prostate cancer
• IM: 1/33
• Gel: 0/25
Type and dose of intramuscular
testosterone not reported. Dose of
Androgel and Testim not reported (data
not provided separately by type)
Wang 2004
•Prostate cancer
• Skin reactions
Three cases of prostate cancer
reported: 1 in 75 mg/d group, 2 in
100 mg/d group
Number of people in each group not
reported
Note: IM = intramuscular injection.
*Reported as polycythemia for the treatment group. Zero count inferred for the control group.
†Composite outcome of all-cause mortality, myocardial infarction, and ischemic stroke.
27
Skin reactions
Of the included non-randomized studies, 5 reported skin reactions (51, 56, 59, 60, 63), ranging from
hematoma at the injection site (intramuscular injection), to rash or acne (Testim 1% gel), to application
site reactions (Androgel 1%) (Exhibit 21). None of the included studies involved treatment with a
testosterone patch.
Exhibit 21: Skin reactions reported in included non-randomized studies
Study
Treatment
(no. in group)
No. of reported
reactions (%)
Did the affected participants
withdraw as a result of the
reaction?
Hajjar 1997
• Testosterone enanthate or
cypionate, IM, 200 mg/2-3 wk
(n = 45)
• Testim 1%, gel, 50 mg/d (NR)
Hematoma at injection site:
testosterone enanthate or
cypionate: 1
Hematoma at injection site was
listed as a reason for discontinuing
testosterone therapy
• Application site erythema:
15
• Application site rash: 7
• Acne: 6
Urticaria
• Andriol: 1
Acne
• Andriol: 1
Forty patients discontinued the
study drug, 1.1% of which were
due to application site reactions
Application site reactions:
• 50 mg/d: 5
• 75 mg/d: 3
• 100 mg/d: 4
Minimal or mild erythema: 11
Moderate erythema: 1
Acne: 12
Local skin irritation:
• Testim 1%: 11
One patient discontinued because
of worsening “minimal erythema
and punctuate rash”; unclear
whether this participant is included
in the count for “minimal or mild”
erythema. No patients
discontinued because of acne
One patient discontinued use of
Testim 1% gel due to local skin
irritation.
Dean 2005
Park 2003
• Placebo (n = 6)
• Andriol, oral, 160 mg/d
(n = 33)
Wang 2004
(NR)
(NR)
(NR)
Taylor 2010
(NR)
Clomiphene citrate, oral, 25100 mg every second day
(n=65)
Comments
Total number of men in each
group not reported (total
number of patients: n = 371)
These adverse events did not lead
to participants withdrawing
Number of men in each
treatment group unknown
(total no. of participants was
163)
Number of men taking either
Androgel or Testim not
reported separately (total no.
taking a testosterone gel was
39)
28
Key Messages
•
Several of the testosterone replacement therapies were associated with a substantive increase
in serum testosterone levels at 3 months.
• Androderm (patch, 5 mg/d), Androgel 1% (gel, 50 mg/d), Androgel 1% (gel, 75 mg/d),
Androgel 1% (gel, 100 mg/d), Testim 1% (gel, 50–150 mg/d) plus sildenafil, Delatestryl
(IM, 200 mg/2wk), and testosterone enanthate (IM, 200 mg/2wk) were associated with
an increase in serum testosterone levels.
• The largest increase in serum testosterone was for Androgel 1% gel (100 mg/d) and Delatestryl (IM,
200 mg/2wk).
•
Overall, no significant improvements in quality of life were identified. However, one study found
a significant improvement in quality of life for Andriol, oral, 120–160 mg/d (24).
•
Overall, no significant improvements in erectile dysfunction were identified. However, two
studies found a significant improvement in erectile dysfunction for testosterone undecanoate,
oral, 160 mg/day (Cavallini (55)) and for Androgel 1%, gel, 50 mg/d (Chiang (14)).
•
Overall, no significant improvements in libido were identified. However, three studies found a
significant difference in libido; two found a deterioration in libido for TRT (Chiang (14) - Androgel
1%, gel, 50 mg/d; Steidle (44) - Testim 1%,gel, 100 mg/d) and one study involving men with type
II diabetes found an improvement (Boyanov (11) - Andriol, oral, 120 mg/d) compared to
placebo.
•
Overall, no significant effects on depression were identified. However, one study by Zhang and
colleagues (24) found a significant improvement in depression for Andriol, oral 120–160 mg/d.
•
In head-to-head comparisons:
• Androgel 1% (gel, 100 mg/d) was associated with more favourable serum testosterone
levels at 3 months than the other testosterone replacement therapies.
• There were no significant differences among the testosterone replacement therapies for quality of life,
erectile dysfunction, libido, and depression.
•
Serious adverse events: testosterone gel (199) vs placebo (195): OR 1.61 (95% CI 0.77–3.36).
•
Other safety data from randomized controlled trials were limited:
• Cardiovascular death: 4 events in the testosterone gel group and zero in the placebo
group.
• Myocardial infarction: 2 events in the testosterone gel group and 1 in the placebo group
• Stroke: 1 event in the testosterone gel group and 1 in the placebo group.
• Prostate cancer: 2 events in the testosterone gel group and 1 in the placebo group; 4
events in the testosterone IM group and 5 in the placebo group.
29
•
Heart disease: 2 events in testosterone group and 4 in the placebo group.
•
Safety data from non-randomized trials were limited and poorly reported:
• Cardiovascular death: not reported
• Myocardial infarction: reported in 1 study (1 event in treatment group, 0 in control)
• Stroke: 1 study (1 event in treatment group, 1 in control)
• Diabetes: 1 study (1 event in treatment group, 0 in control)
• Erythrocytosis: 2 studies (11 events in treatment group, 0 in control)
• Prostate cancer: 5 studies (unable to tabulate due to poor reporting)
•
Overall, skin-related adverse effects ranged from mild skin irritation to rashes and from allergic
contact dermatitis and moderate skin erythema to intense edema and blistering.
30
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61.
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62.
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34
Appendix A: Included Randomized Controlled Trial List
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Amory JK, Watts NB, Easley KA, et al. Exogenous testosterone or testosterone with finasteride increases bone
mineral density in older men with low serum testosterone. J Clin Endocrinol Metab. 2004;89(2):503-510.
Arver S, Sinha-Hikim I, Beall G, Guerrero M, Shen R, Bhasin S. Serum dihydrotestosterone and testosterone
concentrations in human immunodeficiency virus-infected men with and without weight loss. J Androl.
1999;20(5):611-618.
Aversa A, Bruzziches R, Francomano D, Spera G, Lenzi A. Efficacy and safety of two different testosterone
undecanoate formulations in hypogonadal men with metabolic syndrome. J Endocrinol Invest.
2010;33(11):776-783.
Bachman E, Travison TG, Basaria S, et al. Testosterone Induces Erythrocytosis via Increased Erythropoietin
and Suppressed Hepcidin: Evidence for a New Erythropoietin/Hemoglobin Set Point. J Gerontol A Biol Sci
Med Sci. 2014;69(6):725-735.
Basaria S, Coviello AD, Travison TG, et al. Adverse events associated with testosterone administration. N Engl
J Med. 2010;363(2):109-122.
Basaria S, Davda MN, Travison TG, Ulloor J, Singh R, Bhasin S. Risk factors associated with cardiovascular
events during testosterone administration in older men with mobility limitation. J Gerontol A Biol Sci Med Sci.
2013;68(2):153-160.
Basurto L, Zarate A, Gomez R, Vargas C, Saucedo R, Galvan R. Effect of testosterone therapy on lumbar spine
and hip mineral density in elderly men. Aging Male. 2008;11(3):140-145.
Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal
system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin
Endocrinol Metab. 1998;83(9):3155-3162.
Bhasin S, Storer TW, Javanbakht M, et al. Testosterone replacement and resistance exercise in HIV-infected
men with weight loss and low testosterone levels. JAMA : the journal of the American Medical Association.
2000;283(6):763-770.
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37
Appendix B: Characteristics of included RCTs
Study (companion
publication)
Age, mean
(SD), yr
Comorbidities, no (%) per group
Wang 2013, p. 1
(Wang 2001;
Swerdloff 2000;
Burnett 2013)
68.2 (5.2)
NR
Shabsigh 2004, p.
658
57.9 (9.8)
Hypertension
• Placebo: 13 (39%);
• TRT: 12 (32%)
Diabetes
• Placebo 4 (12%)
•TRT: 7 (19%)
Borst 2014, p. E433
TRT: 69.2 (SE
8.0) yr;
placebo:
70.8 (SE 9.7)
yr
Hildreth 2013‡, p.
1891
66 (5)
Spitzer 2012, p. 681
(Spitzer 2013)
Zhang 2012, p. 3806
Indication/specific population
Stated T inclusion
criteria, total
testosterone
(unless otherwise
stated)
Drug, route, dose
Baseline T¶¶ level, mean (SD),
ng/dl
Duration
Men aged ≥ 60 years with T score −2.5
(if no prevalent vertebral fracture) or ≤
−2.0 (if 1 prevalent vertebral fracture) at
the femoral neck, total hip, trochanter,
or lumbar spine and > −4.0 at all sites
< 300 ng/dl
• Placebo, oral
• Andriol 20 mg/d: 218.3 (25.1)
• Andriol 40 mg/d: 214.8 (22.4)
• Placebo: 220.1 (20.7)
24 mo
Men 18–80 yr with ED for ≥ 3 mo, in a
stable sexual relationship with a woman
for ≥ 6 mo, morning serum total T level
of ≤ 400 ng/dl at 2 visits, and nonresponsive to sildenafil monotherapy
≤ 400 ng/dl (83% of
participants had T <
300 ng/dl)
• Placebo, gel
NR
12 wk
Older hypogonadal men
≤ 300 ng/dl
• Delatestryl, IM, 125 mg/wk
• Delatestryl, IM, 125 mg/wk
with Proscar, oral, 5 mg
• Proscar, oral, 5 mg
• placebo
• Delatestryl: 245 (SE: 73)
• Placebo: 264 (SE:92)
12 mo
NR
Community dwelling men ≥ 60 yr
200–350 ng/dl
• Androgel 1%, gel, 25-100
mg/d, no PRT
• Androgel 1%, gel, 25-100
mg/d + PRT
•Placebo, no PRT
•Placebo + PRT
• Androgel 1%, no PRT: 297.7
(43.4)
• Placebo: 294.3 (38.8)
12 mo
TRT: 55.1
(8.3);
placebo:
54.6 (8.5)
Hypertension:
• TRT: 29 (45%); Placebo: 27 (40%)
Diabetes:
•TRT: 13 (21%); Placebo: 14 (22%)
Cardiovascular disease
•TRT: 35 (50%); Placebo: 32 (46%)
Men with ED and low testosterone
Total T < 330 ng/dL
or free T: < 50
pg/mL
• Testim 1% gel, 50– 150 mg/d
+ sildenafil
• Placebo + sildenafil
• Testim 1% + sildenafil: 248 (62)
• Placebo + sildenafil: 254 (68)
14 wk
TRT: 59.4
(6.3);
placebo:
61.1 (7.1)
NR
Men > 50 yr with symptoms of
testosterone deficiency
Total T <8 nmol/L
(230 ng/dL) or free
T < 65 pg/mL if T
between 8 and 12
nmol/L
• Andriol, oral, 120-160 mg/d
• Placebo (Vitamin E/C
capsules)
• Andriol: 7.98 nmol/L (0.73)
• Placebo: 7.73 nmol/L (0.8)
6 mo
DRAFT
38
Sheffield-Moore
2011, E1831
70 (2)
NR
Community-dwelling older men (60–85
yr) with endogenous levels of serum
total testosterone in the lower half of
the normal range
280–500 ng/dL
• Testosterone enanthate, IM,
100 mg/wk
• Cycled testosterone
enanthate, IM, 100 mg/wk§
• Placebo
• Testosterone enanthate: 341
(85)
• Placebo: 344 (85)
5 mo
Aversa 2010, p. 776
57 (8)
Diabetes:
• Testosterone undecanoate: 3
(30%); Placebo: 4 (40%)
Metabolic syndrome and/or type II
diabetes
Total T <3.20 ng/ml
(11 nmol/l)
or free T <250
pmol/l (10 pg/ml)
• Testosterone undecanoate,
oral, 160 mg/d
IM, 1000 mg/12 wk¶
• Placebo
• Testosterone undecanoate: 2.6
ng/mL
• Placebo: 2.6 ng/mL
6 mo
Kenny 2010, p. 1134
77.1 (7.6)
Hypertenstion
• TRT: 22 (15%); Placebo: 24 (15%)
Diabetes
• TRT: 12 (8%); Placebo: 10 (6%)
Coronary artery disease
• TRT: 24 (16%); Placebo: 36 (22%)
Depression
• TRT: 15 (10%); Placebo: 11 (7%)
Older men with low bone mass and
physical frailty
< 350 ng/dL
• Placebo
• Androgel 1%: 380.4 (179.5) ng/dl
• Placebo: 417.8 (192.5) ng/dl
12-24 mo
Basaria 2010, p. 109
(Bachman 2014,
Huang 2013, Basaria
2013, Travison 2011)
TRT: 74 (6);
placebo: 74
(5)
Hypertenstion
Older men with limited mobility
• TRT: 90 (85%); Placebo: 80 (78%)
Diabetes
• TRT: 25 (24%); Placebo: 28 (27%)
Cardiovascular disease
• TRT: 56 (53%); Placebo: 48 (47%)
Obesity (BMI >30)
• TRT: 48 (45%); Placebo: 50 (49%)
Hyperlipidemia
• TRT: 67 (63%); Placebo: 51 (50%)
Total T < 12.1
nmol/L or free T <
50 pg/mL
• Placebo
• Testim 1%: 250 (57)
• placebo: 236 (66)
6 mo
Morales 2009, p.
104
TRT: 59.0
(10.6);
placebo:
60.2 (9.6)
NR
< 12 nmol/L
• Androgel, oral, 160 mg/d**
• Dehydroepiandrosterone
(DHEA), oral, 100 mg/d¶
• Placebo
4 mo
Shores 2009, p. 1009
TRT: 57.1
Dysthymia/minor depression:
Older, hypogonadal men with
• Androgel 1%: 12 (71%) / 5 (29%); subthreshold depression
Placebo: 6 (38%) / 10 (63%)
≤ 280 ng/dL
• Placebo
• Androgel 1%: 291 (108)
• placebo: 267 (98)
12 wk (5.7);
(RCT was
followed by a
12-week openlabel extension
phase during
which all
subjects
received T gel)
NR
Total T: < 300 ng/dl
or total T
“marginally” ≥ 300
ng/dL if free T < 8.7
pg/ml
• Androgel, gel, 50 mg/d
• Placebo
NR
3 mo
placebo:
61.7 (7.0)
Chiang 2009, p. 411
NR
Men 45–70 yr with a primary complaint
of sexual dysfunction
Hypogonadal
DRAFT
39
Emmelot-Vonk,
2009, p. 129
(Emmelot-Vonk
2008, Nakhai-Pour
2007)
67 (5)
Basurto 2008, p. 140
63.2 (7.9)
Chiang 2007, p. 411
Hyperlipidemia:
Aging men with moderately low
testosterone levels
< 13.7 nmol/L
• Placebo
26 wk
NR
Elderly men with low total serum
testosterone concentrations
< 320 ng/dL
250 mg/3wk
• Placebo
• Testosterone enanthate: 301
(32)
• placebo: 310 (37)
12 mo
TRT: 47.9
(17.0);
placebo:
56.1 (14.6)
NR
Hypogonadal
Total T < 300 ng/dl
or free T < 8.7
pg/ml if total T
>300 ng/dl
• Placebo
• Androgel 1%: 213.1 (158.3)
• Placebo: 263.4 (198.1)
3 mo
Marks
2006, p. 2351
Median TRT:
68; placebo:
70
NR
Hypogonadal men aged 44–78 yr with
symptoms of late-onset hypogonadism
< 300 ng/dl
• Delatestryl, IM, 150 mg/2wk
• Placebo
• Delatestryl: median (range): 221
(13-320)
• Placebo: median (range): 252
(144-328)
6 mo
Brockenbrough
2006, p. 251
TRT: 58.9
(14.9);
placebo:
53.0 (17.2)
NR
Hypogonadal male hemodialysis patients
≤ 300 ng/dl
• Placebo
• Testim 1%: 218.9 (64.6)
• Placebo: 201.7 (87.2)
6 mo
Orengo 2005, p. 20
63 (8.5)
All participants had depression
Men aged > 50 yr with treatmentresistant depression
< 350 ng/dl
• Placebo
• Androgel 1%: 2.58 (0.49)
• Placebo: 2.93 (0.65)
12 wk
Cavallini 2004, p.
641
TRT: 60-72
yr; placebo:
61-74 yr
NR
Men with male aging symptoms
Free T: < 6 pg/mL
oral, 160 mg/day
• propionyl-L-carnitine, route
NR, 2 g/day + acetyl-L-carnitine,
route NR, 2 g/d¶
• Placebo
• Testosterone undecanoate: 9.89
nmol/L (1.84)
6 mo
Amory 2004, p. 503
(Page 2005,
Vaughan 2007)
71 (4)
Depression:
• Testosterone enanthate: 3.3
(0.6); Placebo: 5.1 (1.0)
Older men who had serum T below the
range of normal for young adult men
< 12.1 nmol/L
200 mg/2wk
200 mg/2wk + Finasteride, oral,
5 mg‡‡
• Placebo
• Testosterone enanthate:
9.9nmol/L (1.6)
36 mo
Tan 2003, p. 13
TRT: 72.4;
placebo:
68.9
NR
Men with a new diagnosis of Alzheimer’s
disease
< 250 ng/dL
200mg/2wk
• Placebo
(NR)
• Placebo: NR (NR)
12 mo
Boyanov 2003, p. 1
57.5 (4.8)
All participants had diabetes
Men with type 2 diabetes and androgen
deficiency
< 15.1 nmol/l
• No treatment
• Andriol, oral: 9.56nmol/L (2.33)
• No treatment: 10.76mmol/L
(11.20)
3 mo
• Andriol: 47 (41.7%); Placebo: 39
(35.0%)
Hypertension:
• Andriol: 94 (83.3%); Placebo: 85
(76.9%)
40
Steidle 2003, p. 2673
(Seftel 2004)
58.0 (10.3)
NR
Aging men with low serum T and
associated signs and symptoms of
hypogonadism
< 300 ng/dl
• Testim, gel, 50 mg/d
• Testim, gel, 100 mg/d
• Androderm, patch, 5 mg/d
• Placebo
• Testim 1%, 50 mg/d: 233.8 (57.0)
• Testim 1%, 100 mg/d: 232.0
(61.9)
• Androderm: 239.1 (68.9)
• Placebo: 228.5 (80.3)
90 d
McNicholas 2003, p.
69
Testim 50
mg/d: 59.0
(9.5); Testim
100 mg/d:
56.7 (10.3)
NR
Men with low serum testosterone levels
and associated signs and symptoms of
hypogonadism.
≤ 10.4 nmol/L
• Andropatch, patch, 5 mg/d¶
• Testim 1%, 50 mg/d: 7.95
nmol/L (2.17)
• Testim 1%, 100 mg/d:
7.92nmol/L (2.45)
90 d
Ferrando 2003,
p. 358
(Ferrando 2002)
TRT: 68 (3);
placebo: 67
(3)
NR
Healthy older men
< 480 ng/dl
• Testosterone enanthate
50–400 mg/1-2 wk
• Placebo
nmol/L (SE 2.0)
• Placebo: 9.8nmol/L (SE 1.9)
6 mo
Wang 2000, p. 2839
Androderm:
51.1;
Androgel 50
mg/d: 51.3;
Androgel 100
mg/d: 51.0
NR
Hypogonadal men; 35%–45% had
primary hypogonadism (Klinefelter’s
syndrome, anorchia, or testicular
failure); 15–25% had secondary
hypogonadism (Kallman’s syndrome,
hypothalamic pituitary disease, or
pituitary tumor).
≤10.4 nmol/L
• Androderm: 8.22nmol/L (SE
0.55)
• Androgel 1%, 50 mg/d: 8.22
nmol/L (SE 0.53)
• Androgel 1%, 100 mg/d: 8.60
nmol/L (SE 0.55)
180 d (used
first 90d)
Bhasin 2000, p. 763
(Arver 1999)
TRT: 40.8 (SE
1.2);
Placebo:
41.8 (SE 2.5)
All men were HIV- infected
HIV- infected men with low testosterone
levels and weight loss
< 12.1 nmol/L
• Testosterone ethanthate, IM,
100 mg/wk (no exercise)
• testosterone ethanthate, IM,
100mg/wk with exercise
• Placebo (no exercise)
• Placebo (with exercise)
• Testosterone ethanthate (no
exercise): 7.1 nmol/L (SE 0.8)
• Testosterone ethanthate (with
exercise): 7.0 nmol/L (SE 1.2)
• Placebo (no exercise): 6.1nmol/L
(SE 0.7)
• Placebo (with exercise): 7.0
nmol/L (SE 1.0)
16 wk
Dobs 1999, p. 3469
Androderm:
44.3 (11.1):
Delatestryl:
44.9 (11.6)
NR
Hypogonadal men 20–65 yr who had
been receiving TRT (IM) for at least 3
months
≤ 300 ng/dl or ≤
350 ng/dl
(Klienfelters)
• Delatestryl, IM, 200 mg/2wk
• Androderm: 166 (79)
• Delatestryl : 182 (94)
24 wk
Clogue 1999, p. 261
TRT: 68.1
(6.6);
placebo:
65.3 (1.8)
NR
Community-living men > 60 yr who
fulfilled the guidelines recommended by
the WHO for studies on androgen
replacement in older men
< 14 nmol/L
200 mg/2wk: 11.3nmol/L (1.7)
(1.7) nmol/L
• Placebo: 11.6 (0.9) nmol/L
3 mo
Bhasin 1998, p. 3155
NR
All men were HIV- infected
HIV-infected, ambulatory men, 18–60 yr
of age, with serum testosterone levels
below 400 ng/dL
< 400 ng/dl
• Placebo
• Androderm: 258 (50)
• Placebo: 211 (85)
12 wk
Grinspoon 1998 , p.
18 (Grinspoon 2000)
42 (8)
All men were HIV-positive
Androgen deficient men with the AIDS
wasting syndrome
Free T: < 42 pmol/L
300 mg/3wk
• Placebo
nmol/L (5.4)
6 mo
41
Sih 1997, p. 1661
TRT: 65 (7);
placebo: 68
(6)
Hypertension:
• Testosterone cypionate: 4 (24%);
Placebo: 2 (13%)
Diabetes:
Placebo: 1 (7%)
Hyperlipidemia
Placebo: 1 (7%)
Depression:
Placebo: 2 (13%)
Kang 2002, p. 862
58 (8)
Simon 2001, p. 2149
NR
Community-dwelling healthy men ≥ 50
years of age
Bioavailable T: < 60
ng/dl
• Testosterone cypionate, IM,
200 mg/2wk
• placebo
• Testosterone cypionate: 294 (26)
• Placebo: 233 (20)
12 mo
Hypertension:
Men aged with coronary artery disease
• Andriol: 8 (44%); Placebo: 11
(65%)
Diabetes:
•Andriol: 3 (17%); Placebo: 2 (12%)
Coronary artery disease:
• Andriol: 18 (100%); Placebo: 17
(100%)
NR
•Andriol, oral, 160 mg/d
• Placebo
•Andriol: 9.9 pg/mL (3.1)
• Placebo: 13.8 pg/mL (1.8)
12 wk
Diabetes:
• Testosterone gel: 0 (0%);
Placebo: 1 (17%)
< 4 ng/ml
• Testosterone gel 125 mg/d
• Dihydrotestosterone gel, 35
mg/d§
• Placebo
• Testosterone gel: 2.4 (0.1)
• Placebo: 2.7 (0.3)
3 mo
Healthy adult men
Note: ED = erectile dysfunction, PRT = progressive resistance training, SD = standard deviation, SE = standard error, TRT = testosterone replacement therapy, WHO = World Health Organization.
Studies that contained no outcomes of interest were not included in this table: Montano 2007; Sullivan 2005; Drinka 1995.
Cross-over study, data not reported separately by period: Tenover 1992.
*Age not reported for whole population. Calculated by averaging the reported mean for the trial arms.
†Factorial design: patients were randomized to testosterone with or without an exercise component. Data not reported by treatment group.
§Testosterone enanthate was given for a 1 month period, followed by placebo for 1 month, for a total of 5 months. This arm was not included in data analysis.
¶Not an Health Canada–approved TRT product.
**There is no product named “Androgel” that is an oral formulation. This product is believed to be “Andriol” base on the description of the route and dose. This arm has been included as “Andriol” in subsequent analyses.
††This arm was not included in subsequent analyses.
42
Appendix C: Head-To-Head Comparisons — Network Meta-Analysis
The 5 contiguous vertical blocks correspond, respectively, to the five efficacy outcomes: serum testosterone level at 3 months, quality of life,
erectile dysfunction, libido and depression.
•
The green block indicates that the ‘row’ treatment is significantly better than the ‘column’ treatment.
•
The red block indicates that the ‘row’ treatment is significantly worse than the ‘column’ treatment.
•
The grey block indicates that there is no significant difference between the ‘row’ and ‘column’ treatment.
A missing block indicates that the outcome was not available for analysis
Treatments:
1 Androderm, patch, 5 mg/d
2 Androgel 1%, gel, 50 mg/d
10 Testosterone enanthate, IM, 200 mg/2wk
11 Testosterone cypionate, IM, 200 mg/2wk
3 Androgel 1%, gel, 100 mg/d
4 Testim 1%, gel, 50 to 150 mg/d + sildenafil
5 Testim 1%, gel, 50 mg
6 Testosterone, gel, 7.5 g/d
7 Andriol, oral, 120 mg/d
8 Delatestryl, IM, 200 mg/2wk
9 Testosterone enanthate, IM, 100 mg/wk
12 Andriol, oral, 160 mg/d
13 Testim gel, 100 mg/d
14 Andriol, oral, 120-160 mg/d
15 Testosterone undecanoate, oral, 160 mg/d
16 Andriol, oral, 40mg
17 Testosterone enanthate, IM, 300 mg/3wk
18 Androgel 1%, gel 5 mg/d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
1
2
3
4
5
6
43
7
8
9
10
11
12
13
14
15
16
44
17
18
45
Appendix D: Reported Skin Reaction in RCTs
Reported skin reactions in the included randomized controlled trials
Study
Group description
(no. randomized)
No. of reported skin
reactions
Did the affected participant
withdraw from the study as
a result of skin-related
adverse drug events?
Comments
Shores 2009.
(n = 17)
• Placebo (n = 16)
• Androgel 1%: 1
• Placebo: 0
Chiang 2009
(n = 20)
• Androgel 1%: 0
• Placebo: 2
Emmelot-Vonk
2009
(n = 120)
• Andriol: 7
• Placebo 7
Chiang 2007
(n = 20)
• Androgel 1%: 0
• Placebo: 2
Brockenbrough
2006
(n = 19)
• Testim 1%: 2
• Placebo:2
Steidle
2003
(n = 99)
(n = 106)
(n = 102)
• Testim 1% (doses not
reported separately): 17*
• Androderm: 37*
• Placebo: 6*
Yes: 15 patients in the
Androderm group discontinued
treatment because of “local
dermal site reactions”. No
patients in the Testim groups
discontinued treatment because
of an adverse skin reaction.
Some in each group experienced minimal
erythema. Some participants in the Androderm
group experienced minimal erythema, moderate
erythema with sharply defined borders, intense
erythema with or without edema, and intense
erythema with edema and blistering.
McNicholas 2003
(n = 68)
(n = 72)
• Testim 1%, 50 mg/d: 5*
• Testim 1%: 100 mg/d: 4*
Unclear: This study also involved
a non-Health Canada approved
testosterone drug (Andropatch).
The authors reported that some
that discontinued treatment due
to skin reactions, but group
assignment was not clear.
Some patients in the 50 mg/d Testim 1% group
experienced minimal erythema or intense
erythema with or with no oedema. Some patients
in the 100 mg/d Testim 1% testosterone gel group
experienced minimal erythema and moderate
erythema with sharply defined borders.
Wang 2000
(n = 76)
(n = 73)
(n = 78)
• Androderm: 14
• Androgel:
65.8% of treated
participants (data not
reported separately by
dose)
Yes:
16 participants in the
Androderm group discontinued
treatment because of “skin
irritation”
More than half of participants who received
Androgel experienced minimal to severe skin
irritation (“mild erythema to intense erythema with
blisters”). Participants in the Androderm group
experienced moderate to severe skin reactions at
the application site.
Dobs 1999
• Androderm: 17
(n = 33)
•Delatestryl: 1
• Delatestryl, IM, 200 mg/2 wk
(n = 33)
Yes: 3 patients in the Androderm
group discontinued treatment
because of “transient skin
irritation” caused by the patch
About 60% of patients in the Androderm group
experienced “mild to moderate erythema or
pruritus at an application site at least once during
the study”. Two patients experienced allergic
contact dermatitis at the patch application site.
About 33% of patients in the Delatestryl group
experienced “at least one local reaction during the
study (e.g., pain or soreness, bruising, erythema,
swelling, nodules, or furunculosis)”
Yes: 1 participant in the
testosterone group withdrew
because of “skin irritation from
the gel”.
Yes: 2 patients in the placebo
group were “withdrawn from the
study” because of skin-related
adverse events.
Unclear: List of withdrawals does
not explicitly state that patients
who experienced “skin
problems” withdrew from the
study.
Unclear: Reporting not clear as
to whether participants
withdrew because of skin
irritations.
Yes: 1 participant from the
testosterone group withdrew
because of acne
One man in the Testosterone treated group
experienced “skin irritation”
Two men in the placebo group experienced “skin
rash and dermatitis”
A total of 14 men (7 each group) experienced “skin
problems” not described.
Two men in the placebo group experienced
moderate skin erythema (arms, buttocks, head) and
mild skin rash (upper arms)
Two men from each group experienced rash and
acne, which the authors described as “minor side
effects”
46
Bhasin 1998
(n = 20)
• Androderm: 6
• Placebo: 3
Unclear: “Three men withdrew
in the first 15 days of the
treatment
period; 6 additional men
withdrew before completing 10
weeks of treatment”
Eight men (3 in the placebo group and 5
Androderm group) “experienced reactions at the
application site”. One man experienced blister
formation as a result of the Androderm patch,
which the authors stated was “related to rupture of
the patch.” One man experienced an adverse
experience related to “skin and appendages.”
*Data extracted from a figure showing the frequency distribution of men with positive skin irritation scores.
References (skin reactions)
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
Bhasin S, Storer TW, Asbel-Sethi N, et al. Effects of testosterone replacement with a nongenital, transdermal
system, Androderm, in human immunodeficiency virus-infected men with low testosterone levels. J Clin
Endocrinol Metab. 1998;83(9):3155-3162.
Brockenbrough AT, Dittrich MO, Page ST, Smith T, Stivelman JC, Bremner WJ. Transdermal androgen therapy
to augment EPO in the treatment of anemia of chronic renal disease. Am J Kidney Dis. 2006;47(2):251-262.
hypogonadal men mainly through restoring erection: evaluation by IIEF score. Urology. 2009;73(4):762-766.
Chiang HS, Hwang TI, Hsui YS, et al. Transdermal testosterone gel increases serum testosterone levels in
hypogonadal men in Taiwan with improvements in sexual function. Int J Impot Res. 2007;19(4):411-417.
Dobs AS, Meikle AW, Arver S, Sanders SW, Caramelli KE, Mazer NA. Pharmacokinetics, efficacy, and safety of
a permeation-enhanced testosterone transdermal system in comparison with bi-weekly injections of
testosterone enanthate for the treatment of hypogonadal men. J Clin Endocrinol Metab. 1999;84(10):34693478.
Emmelot-Vonk MH, Verhaar HJ, Nakhai-Pour HR, Grobbee DE, van der Schouw YT. Effect of testosterone
supplementation on sexual functioning in aging men: a 6-month randomized controlled trial. Int J Impot Res.
2009;21(2):129-138.
McNicholas TA, Dean JD, Mulder H, Carnegie C, Jones NA. A novel testosterone gel formulation normalizes
androgen levels in hypogonadal men, with improvements in body composition and sexual function. BJU
International. 2003;91(1):69-74.
Shores MM, Kivlahan DR, Sadak TI, Li EJ, Matsumoto AM. A randomized, double-blind, placebo-controlled
study of testosterone treatment in hypogonadal older men with subthreshold depression (dysthymia or
minor depression). J Clin Psychiatry. 2009;70(7):1009-1016.
Steidle C, Schwartz S, Jacoby K, et al. AA2500 testosterone gel normalizes androgen levels in aging males
with improvements in body composition and sexual function. J Clin Endocrinol Metab. 2003;88(6):2673-2681.
Wang C, Swerdloff RS, Iranmanesh A, et al. Transdermal testosterone gel improves sexual function, mood,
muscle strength, and body composition parameters in hypogonadal men. J Clin Endocrinol Metab.
2000;85(8):2839-2853.
47
Appendix E: Included Non-Randomized Study List
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19.
20.
Agarwal PK, Oefelein MG. Testosterone replacement therapy after primary treatment for prostate cancer. J
Urol. 2005;173(2):533-536.
Andrade ES, Jr., Clapauch R, Buksman S. Short term testosterone replacement therapy improves libido and
body composition. Arq Bras Endocrinol Metabol. 2009;53(8):996-1004.
Black AM, Day AG, Morales A. The reliability of clinical and biochemical assessment in symptomatic lateonset hypogonadism: can a case be made for a 3-month therapeutic trial? BJU International.
2004;94(7):1066-1070.
Blick G. Optimal diagnostic measures and thresholds for hypogonadism in men with HIV/AIDS: comparison
between 2 transdermal testosterone replacement therapy gels. Postgrad.Med. 2013;125(2):30-39.
Dean JD, Carnegie C, Rodzvilla J, Smith T. Long-term effects of testim(r) 1% testosterone gel in hypogonadal
men. Rev. 2005;urol.. 7(2):87-94.
Guay AT, Perez JB, Fitaihi WA, Vereb M. Testosterone treatment in hypogonadal men: prostate-specific
antigen level and risk of prostate cancer. Endocr.Pract. 2000;6(2):132-138.
Hajjar RR, Kaiser FE, Morley JE. Outcomes of long-term testosterone replacement in older hypogonadal
males: a retrospective analysis. J Clin Endocrinol Metab. 1997;82(11):3793-3796.
Host C, Bojesen A, Frystyk J, Flyvbjerg A, Christiansen JS, Gravholt CH. Effect of sex hormone treatment on
circulating adiponectin and subforms in Turner and Klinefelter syndrome. European Journal of Clinical
Investigation.40 (3) ()(pp 211-219), 2010.Date of Publication: March 2010. 2010(3):211-219.
Jin B, Conway AJ, Handelsman DJ. Effects of androgen deficiency and replacement on prostate zonal
volumes. Clinical Endocrinology.54 (4) ()(pp 437-445), 2001.Date of Publication: 2001. 2001(4):437-445.
Kalinchenko S, Vishnevskiy EL, Koval AN, Mskhalaya GJ, Saad F. Beneficial effects of testosterone
administration on symptoms of the lower urinary tract in men with late-onset hypogonadism: A pilot study.
Aging Male. 2008;11(2):57-61.
La VS, Calogero AE, D'Agata R, et al. Testosterone therapy improves the clinical response to conventional
treatment for male patients with metabolic syndrome associated to late onset hypogonadism. Minerva
Endocrinologica. 2008;33(3):159-167.
Muraleedharan V, Marsh H, Kapoor D, Channer KS, Jones TH. Testosterone deficiency is associated with
increased risk of mortality and testosterone replacement improves survival in men with type 2 diabetes. Eur.
2013;J. ENDOCRINOL.. 169(6):725-733.
Park NC, Yan BQ, Chung JM, Lee KM. Oral testosterone undecanoate (Andriol) supplement therapy improves
the quality of life for men with testosterone deficiency. Aging Male. 2003;6(2):86-93.
Rhoden EL, Morgentaler A. Influence of demographic factors and biochemical characteristics on the
prostate-specific antigen (PSA) response to testosterone replacement therapy. International Journal of
Impotence Research.18 (2) ()(pp 201-205), 2006.Date of Publication: March 2006. 2006(2):201-205.
Ross RJM, Siyambalapitiya S, Jonsson P, Koltowska-Haggstrom M, Gaillard R, Ho K. Cross-sectional analysis
of testosterone therapies in hypopituitary men on stable pituitary hormone replacement. Clinical
Endocrinology.70 (6) ()(pp 907-913), 2009.Date of Publication: June 2009. 2009(6):907-913.
Shores MM, Smith NL, Forsberg CW, Anawalt BD, Matsumoto AM. Testosterone treatment and mortality in
men with low testosterone levels. J Clin Endocrinol Metab. 2012;97(6):2050-2058.
Strollo F, Strollo G, More M, et al. Low-intermediate dose testosterone replacement therapy by different
pharmaceutical preparations improves frailty score in elderly hypogonadal hyperglycaemic patients. Aging
Male. 2013;16(2):33-37.
Swerdloff RS, Wang C. Three-year follow-up of androgen treatment in hypogonadal men: preliminary report
with testosterone gel. Aging Male. 2003;6(3):207-211.
Taylor F, Levine L. Clomiphene citrate and testosterone gel replacement therapy for male hypogonadism:
Efficacy and treatment cost. Journal of Sexual Medicine.7 (1 PART 1) ()(pp 269-276), 2010.Date of Publication:
January 2010. 2010(1 PART 1):269-276.
Thomson S, Koren G, Van SV, Rieder M, Van Uum SHM. Testosterone concentrations in hair of hypogonadal
men with and without testosterone replacement therapy. Therapeutic Drug Monitoring.31 (6) ()(pp 779-782),
48
21.
22.
23.
24.
25.
2009.Date of Publication: December 2009. 2009(6):779-782.
van den Bergh JP, Hermus AR, Spruyt AI, Sweep CG, Corstens FH, Smals AG. Bone mineral density and
quantitative ultrasound parameters in patients with Klinefelter's syndrome after long-term testosterone
substitution. Osteoporos.Int. 2001;12(1):55-62.
Vigen R, O'Donnell CI, Baron AE, et al. Association of testosterone therapy with mortality, myocardial
infarction, and stroke in men with low testosterone levels. JAMA : the journal of the American Medical
Association. 2013;310(17):1829-1836.
Wang C, Cunningham G, Dobs A, et al. Long-term testosterone gel (AndroGel) treatment maintains beneficial
effects on sexual function and mood, lean and fat mass, and bone mineral density in hypogonadal men. J
Clin Endocrinol Metab. 2004;89(5):2085-2098.
Yaron M, Greenman Y, Rosenfeld JB, et al. Effect of testosterone replacement therapy on arterial stiffness in
older hypogonadal men. Eur J Endocrinol. 2009;160(5):839-846.
Zitzmann M, Depenbusch M, Gromoll J, Nieschlag E. Prostate volume and growth in testosterone-substituted
hypogonadal men are dependent on the CAG repeat polymorphism of the androgen receptor gene: a
longitudinal pharmacogenetic study. J Clin Endocrinol Metab. 2003;88(5):2049-2054.
49
Appendix F: Characteristics of included non-randomized studies
Study
Study
design
Age, mean
(SD), yr
Comorbidities, no (%) per
group
Indication
/specific
population
Stated T
inclusion
criteria, total
testosterone*
Drug, route, dose
Baseline T¶¶ level,
mean (SD), ng/dl
Duration of
treatment
Comment
Dean 2005,
p. 87
Prospective
cohort
58.5 (10.0)
NR
Hypogonadal men
aged 21-81 yrs
≤ 300 ng/dl
• Testim 1%, 50 mg/d
• Testim 1%, 100
mg/d
234 (59.2) ng/dl
Up to 12 mo
Prostate cancer was reported
but not specified as to which
group the event occurred in
Vigen 2013,
p. 1829
Retrospective
cohort
• No
treatment:
63.8 (9.0 yr)
• TRT: 60.6
(7.6)
Hypertension
• TRT: 1101/1223 (90.9%); no
treatment: 6952/7486 (92.9%)
Diabetes
• TRT: 650/1223 (53.2%); no
treatment: 4171/7486 (55.7%)
Men who
< 300 ng/dl
underwent coronary
angiography at a
Veterans Affairs
medical centre
between 2005 and
2001 and who had
total T level
measured
• TRT treatment; dose
not reported
• No treatment
• TRT: 175.5 (62.3)
• No treatment: 206.5
(73.8)
Mean follow-up:
840 d
Patients were categorized as
initiating TRT if they filled a
prescription for a patch, gel
or injectable following
coronary angiography based
on pharmacy-dispensing
data. Patients were assumed
to have continued treatment
until an event occurred or
end of follow-up
Men > 40 yr
who were treated
at a Veterans
Affairs medical
centers and had a
serum total
testosterone level
< 250
• TRT; dose not
reported
• No treatment
• TRT: 160 (62)
• No treatment: 193
(54)
Mean duration:
20.2 (16.7) mo
Non-obstructed CAD
• TRT: 356/1223 (29.1%); no
treatment: 2089/7486 (27.9%)
Obstructed CAD
• TRT: 670/1223 (54.8%); no
treatment: 4497/7486 (60.1%)
Obesity
• Treatment: 703/1223 (57.5% );
no treatment: 4033/7486
(53.9%)
Hyperlipidemia
• TRT: 1051/1223 (85.9%); no
treatment: 6611/7486 (88.3%)
Depression
• TRT: 448/1223 (36.6%); no
treatment: 2641/7486 (35.3%)
Shores
2012, p.
2050
Retrospective
cohort
62.1 (10.6)
Diabetes:
• TRT: 143/398 (35.9%); no
treatment: 250/633 (39.5%)
Coronary artery disease:
• TRT: 80/398 (20.1%); no
treatment: 146/633 (23.1%)
Obesity (BMI > 30):
• TRT: 269/398 (67.6%); no
treatment: 379/633 (59.9%)
< 250 ng/d
DRAFT
50
Wang 2004,
p. 2085
(Swerdloff
4978)
Prospective
cohort
51.5 (0.9)
NR
Men aged 19-68 yr
with diagnosed
hypogonadism
≤ 10.4 nmol/l
(300 ng/dl)
• Androgel 1%, gel,
50 mg/d
75 mg/d
100 mg/d
• Androgel 1, 50
mg/d: 14.1 nmol/L
(1.3)
• Androgel 1% 75
mg/d: 22.4 nmol/L
(2.7)
36 mo
• Androgel 1% 100
mg/d: 25.6 nmol/L
(2.4)
Number of participants for
each group was not reported.
This study was completed
after an initial 6-month
randomized study for an
additional 36 months;
participants had a total of 42
months of gel exposure.
Hajjar 1997,
p. 3793
Retrospective
cohort
TRT: 71.8
(SE 1.7); no
treatment:
69.9 (SE 1.9)
NR
Elderly
hypogonadal men
Bioavailable
Testosterone
≤72 ng/dL
• Testosterone
enanthate or
cypionate, IM,
200mg/2 wk
• No treatment
• TRT: 310.9 (SE 20.0)
• No treatment: 275.5
(SEM 21.1)
24 mo
Blick 2013,
p. 30
Retrospective
cohort
49.5 (8.1)
All men were HIV positive/had
AIDS
Hypogonadal men
with HIV/AIDS
< 300 ng/dl or
free
testosterone <
50 pg/ml
• Androgel 1%, gel, 50
mg/d
• Testim 1%, gel, 50
mg/d
• Androgel 1%: 400
(158)
• Testim 1%: 394
(208)
12 mo
Guay 2000,
p. 132
Retrospective
cohort
40-80 yr
NR
Men with ED and
primary or
secondary
hypogonadism
NR
• Testosterone
enanthate, IM, 200300 mg/2-3 wk
•Testosterone, patch
(non-scrotal), 5 mg/d
•Clomiphene citrate,
oral, 3x/week
Free T*:
• 40–60 yr: 9.7 (2.9)
pg/mL
• 61–80 yr: 8.1 (1.6)
pg/mL
2-3 months
Clomiphene citrate is not
approved by Health Canada;
data were not extracted for
this arm
Rhoden
2006, p. 201
Retrospective
cohort
58.3 (range
42-77)
NR
Hypogonadal men
with negative
prostate biopsy
prior to initiation
of TRT
NR: “All men
presented with
hypogonadal
symptoms, and
had
confirmatory
blood tests
demonstrating
low levels of
either total
testosterone
(TT), free
testosterone
(FT), or both”
• Testosterone, IM,
dose not reported
• Androgel or Testim,
Gel, dose not
reported
• Testosterone, IM:
298 (156.6)
• Androgel or Testim:
293 (89.7)
12 mo
Dose and percentage of gel
not reported
Note: ED = erectile dysfunction, IM = intramuscular injection, NR = not reported.
*Baseline testosterone values reported only for the group of patients who received clomiphene citrate; all included patients had primary or secondary hypogonadism.
DRAFT

TRT Systematic Review Report

Transcription

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